This research seeks to extend current knowledge of the deformability of the human erythrocyte, in both health and disease, and the physiological impact of deformability loss in these cells. Specific aims of this application are: 1. To elucidate the nature of the physical/chemical changes in erythrocytes which cause their sequestration in the spleen and other organs in vivo. 2. To study the deformability of erythrocytes parasitized by different strains of malaria (plasmodium berghei and cynomolgi) at different stages of maturation. 3. To assess in vitro the deformability of erythrocytes in post-splenectomy subjects and in individuals with hereditary spherocytosis and various hemolytic anemias. 4. To determine whether the age of circulating erythrocytes in normal subjects is reflected in their sequestration in vivo. 5. To determine whether erythrocytes from diabetics with proliferative retinopathy and/or in poor metabolic control differ from those of normal subjects in their rheological behavior in vitro and in vivo. Longer term objectives are: 6. To investigate the influence of specific environmental factors on erythrocyte deformability, e.g., platelet-activation products, vasoactive hormones, hyperphysiologic shear stress and pharmacologic agents. 7. To develop and refine mathematical models of the motion and deformation of individual erythrocytes freely suspended in simple shear and pure extensional flows. The methodology is primarily experimental, consisting of (i) microrheologic measurements of erythrocyte deformation in simple shear and pure extensional flows, (ii) physical/chemical characterizations of erythrocytes and erythrocyte membranes, (iii) in vivo perfusions designed to quantify sequestration of erythorocytes in different organs. Mathematical modeling will be pursued with the aim of deducing intrinsic rheological properties of erythrocyte membrane from measurements of cellular elongation, membrane rotation (tank-treading) and transient shape recovery.